Bacterial Factors That Predict Relapse after Tuberculosis Therapy

Roberto Colangeli; Hannah Jedrey; Soyeon Kim; Roy Connell; Shuyi Ma; Uma D Chippada Venkata; Soumitesh Chakravorty; Aditi Gupta; Erin E Sizemore; Lois Diem; David R Sherman; Alphonse Okwera; Reynaldo Dietze; W Henry Boom; John L Johnson; William R Mac Kenzie; David Alland; DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams

doi:10.1056/NEJMoa1715849

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Bacterial Factors That Predict Relapse after Tuberculosis Therapy

Journal article

Open access

Peer reviewed

Bacterial Factors That Predict Relapse after Tuberculosis Therapy

Roberto Colangeli, Hannah Jedrey, Soyeon Kim, Roy Connell, Shuyi Ma, Uma D Chippada Venkata, Soumitesh Chakravorty, Aditi Gupta, Erin E Sizemore, Lois Diem, …

The New England journal of medicine, Vol.379(9), pp.823-833

08/30/2018

DOI: https://doi.org/10.1056/NEJMoa1715849

PMCID: PMC6317071

PMID: 30157391

Abstract

Recurrence

Isoniazid - pharmacology

Area Under Curve

Humans

Antitubercular Agents - pharmacology

Drug Resistance, Bacterial

Male

Tuberculosis - microbiology

Mycobacterium tuberculosis - drug effects

Mycobacterium tuberculosis - isolation & purification

Microbial Sensitivity Tests

Treatment Failure

Tuberculosis - drug therapy

Adult

Female

Isoniazid - therapeutic use

ROC Curve

Rifampin - therapeutic use

Rifampin - pharmacology

Antitubercular Agents - therapeutic use

Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort). In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.).

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Title: Bacterial Factors That Predict Relapse after Tuberculosis Therapy
Creators: Roberto Colangeli - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Hannah Jedrey - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Soyeon Kim - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Roy Connell - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Shuyi Ma - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Uma D Chippada Venkata - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Soumitesh Chakravorty - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Aditi Gupta - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Erin E Sizemore - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Lois Diem - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
David R Sherman - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Alphonse Okwera - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
Reynaldo Dietze - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
W Henry Boom - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
John L Johnson - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
William R Mac Kenzie - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
David Alland - From the Department of Medicine, Rutgers-New Jersey Medical School (R. Colangeli, H.J., U.D.C.V., S.C., A.G., D.A.), and the Department of Biostatistics, Rutgers School of Public Health (S.K., R. Connell), Newark; the Center for Infectious Disease Research, Seattle (S.M., D.R.S.); the Centers for Disease Control and Prevention, Atlanta (E.E.S., L.D., W.R.M.K.); Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda (A.O.); Nucleo de Doencas Infecciosas, Centro de Ciencias da Saude, Universidade Federal do Espirito Santo, Vitoria, Brazil (R.D.); and the Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland (W.H.B., J.L.J.)
DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams
Publication Details: The New England journal of medicine, Vol.379(9), pp.823-833
Date published: 08/30/2018
Grant note: T32 AI007509 / NIAID NIH HHS U19 AI111276 / NIAID NIH HHS R01 AI126788 / NIAID NIH HHS U01 AI065663 / NIAID NIH HHS N01AI95383 / NIAID NIH HHS U19 AI11276 / NIAID NIH HHS N01AI70022 / NIAID NIH HHS
Academic Unit: Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654500404646